A case of adrenocortical carcinoma associated with recurrence after laparoscopic surgery
Kazumi lino*t, Yutaka Okit and Hironobu Sasano*
*Department of Pathology, Tohoku University School of Medicine, Sendai and +Department of Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan
(Received 26 April 1999; returned for revision 4 June 1999; finally revised 5 July 1999; accepted 6 August 2000)
Summary
Laparoscopic adrenalectomy has become increas- ingly popular because of its minimally invasive nature, but guidelines for selection of cases suitable for this surgical procedure have not been established. We report a 52-year-old woman with adrenocortical carcinoma, manifesting as Cushing’s syndrome, trea- ted with laparoscopic adrenalectomy. The tumour was removed in toto and had been histologically diag- nosed as adrenocortical adenoma. However, the patient developed intra-abdominal peritoneal dissemi- nation of carcinoma 15 months after surgery. Review of the histopathological findings of the resected adre- nocortical tumour revealed that the neoplasm met five out of nine histological criteria for adrenocortical malignancy, and was diagnosed as adrenocortical car- cinoma. Histopathological examination of the tumour was also consistent with adrenocortical carcinoma. The patient responded extremely well to chemother- apy, including carboplatin, etoposide and o,p’-DDD (1,1-dichlorodiphenyldichloroethane), and a subse- quent CT (computed tomography) scan 12 months after the start of chemotherapy demonstrated no evi- dence of disease. However, the patient developed neurological impairment, including dysarthria, as a side-effect of o,p’-DDD. The patient died of aspiration pneumonia due to a decreased pharyngeal reflex. Postmortem examination revealed no foci of residual carcinoma. This case report emphasizes the impor- tance of excluing possible adrenocortical malignancy in patients considered for laparoscopic adrenalect- omy, histopathological diagnosis of adrenocortical
Correspondence: Dr Hironobu Sasano, Department of Pathology, Tohoku University School of Medicine, 2-1 Seiryou-machi, Aoba-ku, Sendai, Japan 980-8575. Fax: +81 22 273 5976; E-mail: hsasano@patholo2.med.tohoku.ac.jp
malignancy and careful monitoring for neurotoxicity during o,p’-DDD treatment.
Laparoscopic surgery has developed rapidly due to the minimally invasive nature in surgery, gynaecology and urology (Cuschieri, 1992). The laparoscopic approach has been fre- quently applied to explore and remove the adrenal glands, because of the shorter hospital stay and reduced postoperative analgesic requirements compared to conventional and more invasive adrenalectomy (Nakagawa et al., 1995; Prinz, 1995; Brunt et al., 1996; Wells et al., 1998). However, the inclusion and exclusion criteria for laparoscopic adrenalectomy have not necessarily been established, except possibly for pheochromo- cytoma, huge invasive carcinomas and a history of upper abdominal surgery with severe adhesions (Wells et al., 1998). We report a 52-year-old female diagnosed with adrenocortical carcinoma associated with Cushing’s syndrome. The patient was diagnosed originally as an adrenocortical adenoma and underwent laparoscopic adrenalectomy. The cancer recurred with intraperitoneal seeding of carcinoma cells within 15 months of surgery. The patient responded well to chemotherapy, including o,p’-DDD (1,1-dichlorodiphenyldichloroethane), but died of aspiration pneumonia due to decreased pharyngeal reflex, as a possible neurologic complication of o,p’-DDD treatment.
Case report
A 52-year-old Japanese woman was admitted to Hamamatsu University Hospital, in March 1993, for evaluation of increased appetite, depression, diabetes mellitus and weight gain. Physical examination revealed a rounded face, central obesity (height 152-2 cm, weight 65-0 kg) and high blood pressure (150/ 98 mmHg). Hormonal evaluation revealed elevated serum cortisol levels with an absence of circadian periodicity (613 nmol/l at 0800 h, 541 nmol/l at 1200 hours 687 nmol/l at 1600 h, 640 nmol/1 at 2000 h, 637 nmol/l at 2300h; normal range at 0800 hours 165-607 nmol/dl), undetectable plasma ACTH levels (<1.1 pmol/l; normal range 6-6-13.2 pmol/l) and increased urinary excretion of free cortisol (2980 nmol/day; normal range 30-300 nmol/day). Dexamethasone (Dex) sup- pression test performed by an intravenous infusion of Dex (1 mg/ hr for seven hours) (Biemond et al., 1990) showed no supression of serum cortisol (lowest value 534 nmol/l, respectively).
Abdominal CT scan and magnetic resonance imaging (MRI) both demonstrated a left adrenal mass measuring 5.5x4x 3 cm (Fig. la). Uptake of [1311]-6 6-idiomethyl-19-norcholesterol (NP59) accumulated predominantly in the left adrenal gland. She was subsequently diagnosed with ACTH-independent Cushing’s syndrome due to a left adrenocortical tumour and underwent left laparoscopic adrenalectomy in July 1993 at Hamamatsu University Hospital. The tumour was completely removed without rupture of the capsule by laparoscopic surgery. The gland was easily mobilized without adhesion and vascular supply was identified and ligated without difficulty. A laparo- scopic retrieval basket was used. The left adrenal gland weighed 32.5 g and contained a well-circumscribed and encapsulated solitary tumour, measuring 5 cm in maximum dimension. The tumour was diagnosed as adrenocortical adenoma at initial histopathological examination. Serum cortisol levels became undetectable following adrenalectomy and replacement hydro- cortisone (20 mg/day) was administered. Results of endocrino- logical evaluation 7 months after the operation were almost within normal limits. Her body weight had decreased and the Cushingoid features subsequently disappeared. Glucose toler- ance test was normalized, and hypertension and depression improved considerably. In October 1994, 15 months after the adrenalectomy, the patient noted increased appetite and body weight. In December 1994, plasma ACTH levels became undetectable and serum cortisol level and urinary excretions of both free cortisol (2276 nmol/day; normal range 30-300 nmol/ day) and 17-OHCS (40.8 umol/day; normal range 5.5-2.8 umol/ day) were elevated. Abdominal CT scan and MRI in April 1995 demonstrated an irregular-shaped and heterogeneous mass measuring 8×5 cm in the left retroperitoneal space behind the spleen and multiple nodular lesions measuring less than 1 cm on the surface of the liver (Fig. 1b) and pelvic wall, consistent with recurrence and metastasis of a malignant adrenocortical tumour. In April 1995, exploratory laparotomy was performed. An irregular-shaped tumour extending from the abdominal cavity into the retroperitoneal space and numerous foci of nodular metastasis in the mesentery, greater omentum and wall of the pelvic cavity were detected. There was no ascitic fluid. During the laparotomy, one of the nodular peritoneal masses was biopsied. Review of the histology from the original adrenal tumour and peritoneal masses confirmed a diagnosis of adrenocortical carcinoma with intra-abdominal dissemination.
Chemotherapy was subsequently started with carboplatin 300 mg/m2 for one day and etoposide 100 mg/m2 for three days by intravenous infusion every 10 weeks. o,p’-DDD was also started orally in April 1995. The patient received an initial o,p’-DDD dose of 3 g/day which was gradually increased up to 9 g/day. She was on o,p’-DDD treatment for a total of 70 days.
After three courses of chemotherapy, an abdominal CT scan
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in September 1995 demonstrated a reduction in the volume of the peritoneal tumour. CT images in May 1996, 13 months after the initiation of chemotherapy showed no evidence of both the main retroperitoneal tumour and nodular lesions on the surface of the liver (Fig. 1c). In August 1995, four months after chemotherapy, serum cortisol level became undetectable and
@ 2000 Blackwell Science Ltd, Clinical Endocrinology, 53, 243-248
plasma ACTH level was elevated to 17.5-22.0 pmol/l (at 0800 h) with supplemental glucocorticoid in the form of dexamethasone 1 mg/day. Her Cushingoid features also dis- appeared completely.
Severe nausea and appetite loss, however, were noted, possibly as side-effects to the chemotherapy. In June 1995, the patient started to complain of various neurological symptoms including lethargy, hypersalivation, disturbance of movement and dysarthria. Neither MRI or CT images of the brain revealed no metastatic lesions or other abnormalities. The dose of o,p’-DDD was gradually reduced from 9 g/day to 3 g/day. However, there was no improvement in these neurological symptoms.
The patient was followed carefully for 5 months after discharge. In August 1996, she developed acute respiratory failure without any obvious inducing factor following a meal at home, and was pronounced dead at the emergency room of Hamammatsu University Hospital.
Histopathological findings
The tumour was composed of compact cells demonstrating hyperchromasia and severe atypia of the nuclei with occasional nucleoli (Fig. 2a). These tumour cells formed nests or trabecule. Five out of nine histopathological criteria of adrenocortical malignancy proposed by Weiss (1984), such as the presence of sinusoidal invasion, eosinophilic compact cytoplasm, nuclear atypia, diffuse architecture and confluent necrosis were detected. Therefore, this tumour was diagnosed as an adrenocortical carcinoma. Ki-67 and topoisomerase IIa (topolla) labelling index (LI) or percentage of positive cells in this tumour which represents cell proliferation activity (Yabuki et al., 1996; Iino et al., 1997) were 4.25 and 2.95, respectively, consistent with those of adrenocortical malignancy (lino et al., 1997). Histo- pathological features of tumour cells in the peritoneum (Fig. 2b) were similar to those of the primary lesion. Tumour cells infiltrated into peritoneal adipose tissue, but no foci of stromal reaction including desmoplasia and lymphocytic infiltration were detected. No foci of vascular invasion were detected in these foci of peritoneal dissemination. Ad4 BP immunoreactivity, which can serve as an immunohistochemical marker of steroidogenic cells (Morohashi et al., 1992; Sasano et al., 1995b), was detected in almost all the tumour cells, both in the primary and disseminated lesions. Immunoreactivity of steroidogenic enzymes including P450scc (side chain cleav- age), 36-HSD (hydroxysteroid dehydrogenase), P450c21 (21-hydroxylase), P450c17 (178-hydroxylase), P450c11 (116- hydroxylase) and DHEA-ST (dehydroepiandrosterone sulpho- transferase) (Sasano et al., 1993; Sasano et al., 1995a) was also detected in tumour cells of both the primary and disseminated lesions.
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Autopsy findings
No residual carcinoma was detected in the abdominal cavity and retroperitoneal space, either macroscopically or micro- scopically. Ascitic fluid was undetectable and the mesenterium and omentum, which demonstrated carcinoma dissemination on previous CT scans, revealed no abnormalities.
Light microscopic examination of the peritoneum, mesen- terium and omentum also revealed no evidence of residual carcinoma. There were no foci of distant metastasis of car- cinoma in other organs including the lung and liver. Aspiration pneumonia was detected in both right and the left lungs and this was considered the main cause of death.
Discussion
There are three clinically interesting and important features in this case. These are summarized as follows: (1) recurrence of adrenocortical tumour manifesting as peritoneal dissemination after laparoscopic adrenalectomy (2) difficulty of discerning malignancy in resected adrenocortical neoplasms, and (3) possible efficacy and side-effects of chemotherapy, especially o,p’-DDD in patients with adrenocortical carcinoma.
In recent years, laparoscopic adrenalectomy has become increasingly popular. Clinically apparent primary or metastatic invasive adrenal malignancy is considered an absolute con- traindication for laparoscopic adrenalectomy because extensive en bloc surgery and node dissection are required (Lacroix, 1998). However, Nakagawa et al. (1995) advocated its use in removal of adrenocortical malignancy. It has been well recognized that metastatic seeding of tumour cells is one of the most-feared complications following biopsies or surgical removal of malignancies. In laparoscopic surgery, an increasing number of cancer recurrence or seeding in abdominal wall and/or port sites after resection of the tumour has been reported in gall bladder carcinoma (Pezet et al., 1992; Fong et al., 1993; Sailer et al., 1995), colorectal carcinoma (Cirocco et al., 1994; Jacquet et al., 1995), and other malignant tumours (O’Rourke et al., 1993; Johnstone et al., 1996). In addition, Lacroix et al. (1998) recently reported that three out of 100 patients undergoing laparoscopic adrenalectomy were asso- ciated with incomplete resection of the adrenal glands. The factors which may enhance dissemination and tumour implan- tation in laparoscopic surgery compared to open surgery are summarized as follows: (i) increased handling and exfoliation of malignant cells (ii) the presence of a CO2 pneumoperitoneum which may increase nutrient supply by capillary vasodilatation at the port sites and enhance the growth of exfoliated tumour cells, and (iii) creation of multiple raw wounds which could harbour multiple implantation sites (Johnstone et al., 1996). No port site recurrence was noted in this case, in contrast to reported cases of gastrointestinal malignancies associated with postoperative recurrence described above, but our patient developed peritoneal seeding 15 months after surgery. The lesions were located only in the peritoneum and no foci of distant metastasis were noted on abdominal CT. In addition, histopathological findings, including Ad4BP immunoreactivity in the peritoneal lesions, were consistent with dissemination without vascular invasion and ascites. The tumour had been resected completely without any injury to the capsule. There- fore, these findings suggest that intraperitoneal dissemination of the tumour may occur as a result of laparoscopic surgery. However, it is well-known that it is almost always impossible to resect malignant adrenocortical tumour completely and one must assume that micrometastases are present in various
organs and will become clinically apparent within months after resecting adrenocortical carcinoma (Orth & Kovacs, 1998) Therefore, it is also possible that undetectable peritoneal spread was present at the time of surgery. This is the first reported case of a tumour cell dissemination after laparoscopic adrenalec- tomy, but the number of such cases may increase as this surgical approach becomes more widespread. Thus, laparo- scopic adrenalectomy should not be performed if there is any possibility of adrenocortical malignancy in the course of preoperative evaluation, regardless of the size of the adrenal lesions, because it is practically impossible to make the diagnosis of adrenocortical carcinoma prior to surgery.
In adrenocortical neoplasms, morphological features that are generally effective in discerning malignancy in other organs such as gastrointestinal tracts are often not helpful in the histopathological diagnosis of carcinoma (Weiss, 1984; Sasano et al., 1993; lino et al., 1997). Resected adrenocortical tumour in this case had been initially diagnosed as adrenocortical adenoma. Criteria derived from multivariate analysis have been proposed to discern malignancy in resected specimens of adrenocortical neoplasms. Among these criteria, Weiss (1984) demonstrated reasonable effectiveness in the diagnosis of the great majority of cases, including this reported case. In addition, immunostaining of various cell proliferation associated markers such as Ki-67 and Topo Ila examined in this study demonstrated efficacy in the differential diagnosis between adenoma and carcinoma (Iino et al., 1997). Therefore, surgical pathologists involved in the evaluation of resected adrenocortical tumours should at least attempt to employ Weiss’s criteria of adrenocortical malignancy (Weiss, 1984), which requires only histopathological findings.
Clinical efficacy of adjuvant postoperative chemotherapy for adrenocortical carcinoma has been in dispute. o,p’-DDD is the only medication with established effectiveness, at least in advanced adrenocortical carcinomas, and is widely employed (Hutter & Kayhoe, 1966; Vassilopoulou-Sellin et al., 1993). The use of cisplatin, either as a single agent or in multiple-drug combinations, has also demonstrated temporary improvement in several reported cases of adrenocortical carcinoma (Chun et al., 1983; Burgess, 1995; Zidan et al., 1996). We employed o,p’-DDD, carboplatin, one of the cis-platinum derivatives with less renal toxicity, and etoposide, one of the topoisomerase II inhibitors in this case, and the patient responded remarkably well to these agents. Both primary and disseminated lesions had relatively high score of intratumoral topolla expression. Topolla is known not only as a marker of proliferative activity, but also as a target of various anticancer drugs including etoposide (Zijlstra et al., 1990). In addition, increased topolla expression is also related to the reponse to cisplatin based chemotherapy (Zijlstra et al., 1990). Therefore, the marked response to chemotherapy in our case study may be related to
increased topolla expression in carcinoma cells, but this awaits further investigation for clarification.
The patient died of unexpected acute respiratory failure caused by aspiration pneumonia. Clinically effective serum levels of o,p’-DDD make various side-effects of this drug unavoidable, although low doses of o,p’-DDD treatment have been demonstrated to offer prolonged disease-free survival in patients with adrenocortical carcinoma. (Dickstein et al., 1998). In addition, o,p’-DDD accumulates in lipid-rich tissues because of its lipophyllic nature (Zidan et al., 1996) and is known to cross the blood brain barrier (Slooten et al., 1982). Therefore, the effect on central nervous system function is inevitable and unfortunately, one of the most serious and frequent medical complications of o,p’-DDD treatment. Lanser and colleagues reported that all the patients treated with o,p’-DDD suffered from neuropsychological and that the severity of symptoms was generally in proportion to the serum level of o,p’-DDD (Lanser et al., 1992). The patient in our study also suffered from these neurological side-effects, including hypersalivation and dysar- thria. Therefore, aspiration pneumonia, which was considered as the cause of her death may be related to decreased pharyngeal and/or laryngeal reflexes, an associated side-effect of o,p’-DDD treatment. Neurotoxicity should be carefully monitored by attending physicians throughout the course of o,p’-DDD therapy.
Acknowledgements
The authors appreciate excellent technical assistance of Ayako Yonechi, Akio Ohkura and Katsuhiko Ono, Department of Pathology, Tohoku University School of Medicine, Sendai, Japan. and technical advice from Dr Kazuo Suzuki, Department of Urology, Hamamatsu University School of Medicine. A part of this case was presented in abstract form (Journal of Urology, 157, 2239, 1997). The authors also appreciate editing of the manuscript by Mr Andrew David Darnel (Tohoku University School of Medicine, Sendai, Japan).
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